1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative or salt thereof

ABSTRACT

To provide a compound having a superior arginine vasopressin antagonism. A novel 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel1,4,5,6-tetrahydroimidzo[4,5-d]benzazepine derivative or a salt thereofuseful as a drug, especially an arginine vasopressin receptor antagonistand to a drug comprising the compound as an active ingredient.

BACKGROUND ART

Arginine vasopressin (AVP) is an antidiuretic hormone of a peptidecomprising 9 amino acids as biosynthesized and secreted in ahypothalamohypophysial system and is known to have an action to promotewater reabsorption in a kidney distal uriniferous tubule, contract ablood vessel and elevate a blood pressure and to act as aneurotransmitter, etc. in a brain.

As a receptor of AVP, there are known three kinds of subtypes of V_(1A),V_(1B) and V₂. An AVP receptor antagonist to competitively inhibit thebinding to the V_(1A) and/or V₂ receptor of AVP is expected as a drugfor suppressing contraction of a vascular smooth muscle and suppressingpressure rise or as a drug for suppressing water reabsorption in akidney collecting tubule, or as a drug having a combination of theseactions (see NIPPONRINSHO, Vol. 58, Special Issue, “Hypertension (theLast Volume)”, pp. 292-296 (2000)).

On the other hand, with the diversification of medical treatment and theage advance, it has become uncommon to use a drug singly, and in themost case, a plurality of drugs are administered simultaneously or whileshifting the administration time. This is also applicable in the fieldof the AVP receptor antagonist. The drug is inactivated in a liver dueto the action of drug metabolizing enzymes and converted into ametabolite. Among these drug metabolizing enzymes, cytochrome P450 (CYP)is the most important. CYP includes many molecular species. When aplurality of drugs metabolized from CYP of the same molecular speciescompete on the metabolizing enzyme thereof, it is considered that thedrug receives some metabolic inhibition depending on the affinity of thedrug with CYP. As a result, drug interactions such as rise ofconcentration in blood and prolongation of half-life in blood arerevealed.

Such drug interactions are not preferred except the case where the drugis used with the intention of revealing an additive action orpotentiation, and there may be the case where an unexpected side effectis revealed. Accordingly, it is demanded to create a drug having a lowaffinity with CYP and a little possibility of the drug interaction.

Hitherto, as the foregoing AVP receptor antagonist, compounds of apeptide type and compounds of a non-peptide type have been synthesized(see, for example, JP-A-2-32098, WO 91/05549, EP0382185, WO 93/03013, WO95/03305, WO 95/06035, and WO 97/15556).

Among them, WO 95/03305 discloses that a condensed benzazepinederivative represented by the following general formula or its salt isuseful as an AVP receptor antagonist.

(In the formula, the symbols are as defined in the patent document.)

That is, this patent document describes some condensed benzazepinederivatives and salts thereof but does not disclose at all the compoundsof the invention, wherein the ring B represents an optionallysubstituted nitrogen-containing aromatic 5-membered ring having at leastone nitrogen atom and further optionally having one oxygen or sulfuratom; R¹ represents a hydrogen atom; A represents —NHCO-(CR³R⁴)_(n)-; nis 0; and the ring C represents an optionally substituted benzene ring.Further, this patent document describes the V₁ and/or V₂ receptorantagonism of AVP but does not mention the inhibition activity againstthe drug metabolizing enzyme CYP.

As described previously, as the AVP receptor antagonist, the compoundsas described in the above-cited patent documents are known. But, it isan important problem from the standpoint of medical treatment to createa more superior AVP receptor antagonist and to create an AVP receptorantagonist free from side effects based on the inhibition of the drugmetabolizing enzyme CYP.

DISCLOSURE OF THE INVENTION

The present inventors further made extensive and intensiveinvestigations with respect to compounds having an antagonism againstthe AVP receptor. As a result, it has been found that a novel1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative of the inventionhas a superior antagonism against the AVP receptor and has a lowerinhibition activity against the drug metabolizing enzyme CYP3A4, leadingto accomplishment of the invention.

Specifically, according to the invention, there is provided a novel1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative represented bythe following general formula (I) or a pharmaceutically acceptable saltthereof, which is useful as an AVP receptor antagonist.

(In the formula, the ring D represents phenylene or pyridinediyl; X andY may be the same or different and each represents CH or N; and R¹, R²and R³ may be the same or different and each represents a hydrogen atom,a hydroxyl group, a halogen, or a lower alkyl, hereinafter the same.)

Compounds represented by the foregoing general formula (I), wherein thering D represents 1,4-phenylene, pyridine-2,5-diyl, orpyridine-3,6-diyl, or pharmaceutically acceptable salts thereof arepreferable. Compounds represented by the foregoing general formula (I),wherein the ring D represents 1,4-phenylene, pyridine-2,5-diyl, orpyridine-3,6-diyl; X and Y each represents CH; and R¹ represents ahydrogen atom, or pharmaceutically acceptable salts thereof are morepreferable. Compounds represented by the foregoing general formula (I),wherein the ring D represents 1,4-phenylene; X and Y each represents CH;R¹ represents a hydrogen atom; and R² and R³ each represents a hydrogenatom, or pharmaceutically acceptable salts thereof are the mostpreferable.

Particularly preferred examples of the compounds include:

-   N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,-   N-{3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benz    azepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,-   2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benz    azepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,-   N-{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-2-pyridyl}biphenyl-2-carboxamide,-   N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-3-pyridyl}biphenyl-2-carboxamide,-   N-{2-hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]be    nzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, and

pharmaceutically acceptable salts thereof.

The 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative having anantagonism against the AVP receptor according to the invention isstructurally characterized in that a 6-membered aromatic ring havingnitrogen at the 2-position thereof is substituted at tbe 2-position ofthe imidazobenzazepine ring. Such a structural characteristic achieves areduction of the affinity with the drug metabolizing enzyme CYP3A4.

Further, according to the invention, there is provided a pharmaceuticalcomposition comprising, as an active ingredient, a1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative represented bythe foregoing general formula (I) or a pharmaceutically acceptable saltthereof. Concretely, the invention provides a pharmaceutical compositionas an arginine vasopressin receptor antagonist, which comprises, as anactive ingredient, a 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepinederivative represented by the foregoing general formula (I) or apharmaceutically acceptable salt thereof.

Moreover, according to the invention, there is provided a therapeuticdrug for heart failure or a therapeutic drug for hyponatremia, whichcomprises, as an active ingredient, a1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative represented bythe foregoing general formula (I); a compound represented by theforegoing general formula (I), wherein the ring D represents1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl; a compoundrepresented by the foregoing general formula (I), wherein the ring Drepresents 1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl, X andY each represents CH, and R¹ represents a hydrogen atom; a compoundrepresented by the foregoing general formula (I), wherein the ring Drepresents 1,4-phenylene, X and Y each represents CH, R¹ represents ahydrogen atom, and R² and R³ each represents a hydrogen atom;

-   N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbon    yl]phenyl}biphenyl-2-carboxamide;-   N-[3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl]biphenyl-2-carboxamide;-   2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide;-   N-{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbon    yl]-2-pyridyl}biphenyl-2-carboxamide;-   N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbon    yl]-3-pyridyl}biphenyl-2-carboxamide;-   N-{2-hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepi    ne-6-carbonyl]phenyl}biphenyl-2-carboxamide; or a pharmaceutically    acceptable salt thereof.

The compounds of the invention will be further described below.

In this description, the term “lower alkyl” means a linear or branchedcarbon chain having from 1 to 6 carbon atoms (C₁₋₆), and specificexamples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,pentyl, neopentyl, and hexyl. Of these are preferable C₁₋₃ alkylsincluding methyl, ethyl and isopropyl, with methyl and ethyl beingparticularly preferred.

Examples of the “halogen” include a fluorine atom, a chlorine atom, abromine atom, and an iodine atom.

Each of the foregoing substituents R¹, R² and R³ may be bound to anyposition of each ring, but it is desired that R³ is bound to the ortho-or para-position.

The compounds represented by the general formula (I) may possibly havean asymmetric carbon atom depending on the kind of the substituent(s),and optical isomers may be present based on this. The invention includesall of mixtures or isolated compounds of these optical isomers.

Further, with respect to the compounds of the invention, positionisomers based on the imidazole fused on the benzazepine ring may beconsidered. The invention includes all of mixtures or isolated compoundsof these position isomers.

Moreover, the compounds of the invention may possibly form anacid-addition salt. The invention includes such a salt so far as theyare a pharmaceutically acceptable salt. Specifically, examples includeacid addition salts of an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid; and acid addition salts of an organic acid such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, aspartic acid, and glutamic acid. In addition,the invention includes various hydrates, solvates and crystalpolymorphisms of the compound of the invention and its pharmaceuticallyacceptable salt. Incidentally, the compound of the invention includesall of so-called prodrugs, i.e., compounds that will be metabolized andconverted into the compound of the foregoing general formula (I) or itssalt within a living body. As the group to form the prodrug according tothe invention are enumerated those groups described in Prog. Med., 5,2157-2161 (1985) and Iyakuhin No Kaihatsu (Development of Drugs), Vol.7, “Molecular Design”, 163-198 (1990), by Hirokawa Publishing Co.

Production Process:

The compound of the invention and its pharmaceutically acceptable saltcan be produced through application of various known synthesis processesby utilizing the characteristic features based on the basic skeletonthereof or kinds of the substituents. Representative productionprocesses will be enumerated below. Incidentally, in some case, it iseffective on the production technology that depending on the kind of afunctional group, the functional group is replaced by a protectivegroup, i.e., a group that can be readily converted into the functionalgroup in the state of the starting materials or intermediates.Thereafter, if desired, the protective group is removed, therebyenabling to obtain the desired compound. Examples of such a functionalgroup include a hydroxyl group and a carboxyl group. Examples of theprotective group thereof include the protective groups as described inGreene and Wuts, Protective Groups in Organic Synthesis(third edition),and these may be properly used depending on the reaction condition.

Further, as other process, a process in which in a benzyl etherprotected material of a hydroxyl group, pentamethylbenzene is applied ina strongly acidic solution such as trifluoroacetic acid, therebyundergoing deprotection can be enumerated.

This production process is a process in which an optionally protectedsubstituted aromatic carboxylic acid represented by the formula (II) orits reactive derivative and an optionally protected benzazepinederivative represented by the formula (III) or its salt are subjected toamidation in an ordinary manner, and the protective group(s) is removed,if desired, to produce the compound (I) of the invention.

Examples of the reactive derivative of the compound (II) include usualesters such as methyl esters, ethyl esters, and tert-butyl esters; acidhalides such as acid chlorides and acid bromides; acid azides; activeesters with N-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccimide,etc.; symmetric acid anhydrides; and mixed acid anhydrides with an alkylcarbonate, p-toluenesufonic acid, etc.

Further, when the compound (II) is reacted in a liberated acid orreacted without isolating the active ester, it is suitable to use acondensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole,diphenylphosphoryl azide, diethylphosphoryl cyanide, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

The reaction varies depending on the reactive derivative and thecondensing agent to be used but is usually carried out in an organicsolvent that is inert to the reaction, such as halogenated hydrocarbonssuch as dichloromethane, dichloroethane, and chloroform, aromatichydrocarbons such as benzene, toluene, xylene, ethers such as ether andtetrahydrofuran, esters such as ethyl acetate, acetonitrile,N,N-dimethylformamide, and dimethyl sulfoxide, under cooling, or at atemperature of from cooling temperature to room temperature, or at atemperature of from room temperature to an elevated temperature.

Incidentally, in some case, it is advantageous for making the reactionproceed smoothly that the reaction is carried out by using an excessiveamount of the compound (II) or in the presence of a base such asN-methylmorpholine, trimethylamine, triethylamine, N,N-dimethylaniline,pyridine, 4-(N,N-dimethylamino)pyridine, picoline, and lutidine.Further, a salt comprising a weak base and a strong acid, such aspyridine hydrochloride, pyridine p-toluenesulfonate, andN,N-dimethylaniline hydrochloride, may be used. In the case, theimidazole ring fused with the benzazepine forms a slat together with thestrong acid, and the liberated weak base functions as a catalyst.Pyridine may be used as the solvent.

Especially, it is suitable to carry out the reaction in a solvent suchas acetonitrile and N,N-dimethylformamide in the presence of a base suchas pyridine and N,N-dimethylaniline or a salt such as pyridinehydrochloride.

(In the formulae, one party of Y¹ and Y², and Y³ and Y⁴ represents anoxo group (═O), and the other groups represent a halogen atom and ahydrogen atom

The production process is a process in which an optionally protectedhaloketone represented by the formula (IV) and an optionally protectedamidine represented by the formula (V) or its salt are cyclized in anordinary manner, and the protective group(s) is removed, if desired, toproduce the compound (I) of the invention.

In this reaction, in some case, the corresponding amidine forms a salttogether with an acid. Further, in order to promote the reaction, thereaction may be carried out in the presence of an inorganic base such assodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate, asalt of a weak base and a strong acid, or an organic base such aspyridine, diisopropylethylamine, and 1,5-diazabicyclo[4.3.0]non-5-ene.As the solvent to be used for the reaction, are preferable solvents thatare inert to the reaction, such as alcohols such as methanol, ethanol,and 2-propanol, ethers such as ether, tetrahydrofuran, and dioxane,halogenated hydrocarbons such as dichloromethane, chloroform, and carbontetrachloride, acetonitrile, dimethylformamide, and dimethyl sulfoxide.The reaction temperature is preferably from room temperature to arefluxing temperature of the solvent. If desired, the reaction iscarried out under an elevated pressure.

Incidentally, in this reaction, an oxazole may possibly be formed. Inthis case, when the reaction is carried out under the condition ofadding ammonium carbonate, ammonium acetate, a formamide, etc. in anammonia gas stream, the imidazole can be given as a main product.

The starting compound (IV) that is used for this reaction can beproduced by amidating an optionally protected aromatic carboxylic acid(VI) or its reactive derivative and an optionally protected benzazepinederivative (VII) or its salt in the same manner as in the firstproduction process and then exerting a halogenating agent, as shown inthe following reaction scheme (if desired, the protective group(s) isremoved at an arbitrary stage). Incidentally, the aromatic carboxylicacid (VI) can be produced by amidating a corresponding, optionallyprotected 2-phenylbenzoic acid (IX) or its reactive derivative and acorresponding, optionally protected amino aromatic carboxylic acid (X)or its salt in the same manner as in the first production process.

(In the formulae, one party of Y⁵ and Y⁶, and Y⁷ and Y⁸ represents anoxo group (═O), and the other party each represents a hydrogen atom

With respect to the first half amidation, the kind of the reactivederivative and the reaction condition are identical with those of thefirst production process.

As the halogenating agent that is used in the halogenation step, anyhalogenating agents that are usually used for halogenation of saturatedcyclic ketones can be used. Suitable examples include metal reagentssuch as copper(II) halides such as copper(II) bromide and copper(II)chloride; and perbromides of pyridine, α-pyrrolidone, quaternaryammonium, dioxane, etc., such as dioxane dibromide,phenyltrimethylammonium tribromide, pyridium hydrobromide perbromide,and pyrrolidone hydrotribromide. Further, single halogen such aschlorine and bromine, or hydrogen halides such as hydrogen chloride andhydrogen bromide can also be used.

In the reaction using the metal reagent or perbromide, it is usuallyadvantageous to react the compound (VIII) with the halogenating agent inan organic solvent that is inert to the reaction, such as halogenatedhydrocarbons such as dichloromethane, chloroform, and carbontetrachloride, ethers such as ether, tetrahydrofuran, and dioxane,alcohols such as methanol, ethanol, and 2-propanol, aromatichydrocarbons such as benzene, toluene, and xylene, acetic acid, andethyl acetate, or in water, or in a mixed solvent thereof and in theoptional presence of a small amount of a catalyst such as hydrogenhalides at a temperature of from room temperature to an elevatedtemperature.

Further, the desired compound can be obtained by reacting the compound(VIII) with a single halogen as the halogenating agent in a solvent thatis inert to the reaction, such as halogenated hydrocarbons such asdichloromethane, chloroform, and carbon tetrachloride, ethylene glycol,and acetic acid, or by reacting the compound (VIII) with a hydrogenhalide as the halogenating agent in an acidic solution or a basicsolution (such as a sodium hydroxide solution). At this time, thereaction temperature is preferably from −30° C. to the refluxingtemperature of the solvent to be used.

The thus produced compound of the invention is isolated and purified asa free form or as a salt after subjecting to salt formation in anordinary manner. The isolation and purification are carried out byapplying a usual chemical operation such as extraction, concentration,distillation, crystallization, filtration, recrystallization, andvarious kinds of chromatography.

Various isomers can be isolated in an ordinary manner by utilizing adifference in physicochemical properties among the isomers. For example,in the case of racemic mixtures, the racemic compound can be introducedinto an optically pure isomer by a general racemic resolution methodsuch as a method in which the racemic compound is introduced into adiastereomer salt with a general optically active acid such as tartaricacid, which is then subjected to optical resolution. Further, themixture of diastereomers can be separated by fractional crystallizationor various kinds of chromatography. Moreover, it is possible to produceoptically active compounds by using a proper optically active startingmaterial.

INDUSTRIAL APPLICABILITY

The compound of the invention and its salt have a superior antagonismagainst arginine vasopressin V_(1A) and V₂ receptors.

Accordingly, the compound of the invention has actions of profile basedon such actions, such as water diuresis action, urine eliminatingaction, factor VIII secretion inhibiting action, vasodilation action,cardiac function acceleration action, mesangial cell contractioninhibiting action, mesangial cell proliferation inhibiting action,hepatic gluconeogenesis inhibiting action, platelet aggregationinhibiting action, aldosterone secretion inhibiting action, endoserinproduction inhibiting action, central buffer action, renin secretionregulating action, memory regulating action, body temperature regulatingaction, and prostaglandin production regulating action; is useful as acharacteristic water diuretic, urine eliminant, vasodilator, depressor,drug for heart failure, drug for renal failure, or anticoagulant; and iseffective for prevention and/or therapy of heart failure, hyponatremia,syndrome of inappropriate antidiuretic hormone (SIADH), renal diseases(such as nephrosis, nephritis, diabetic nephropathy, and acute orchronic renal failure), brain edema, ascites, hepatic cirrhosis, etc.

Further, since the compound of the invention and its salt have anextremely low inhibition action against the drug metabolizing enzymeCYP3A4, they have a low possibility to cause drug interaction with otherdrugs to be metabolized through CYP3A4 as compared with known1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivatives. Accordingly,the compound of the invention and its salt are superior from thestandpoint that they can be safely used for combined therapy with otherdrug. Examples of the drugs to be metabolized through CYP3A4 includesimvastatin, lovastatin, fluvastatin, atorvastatin, midazolam,nifedipine, amlodipine, and nicardipine (see SOGORINSHO (OverallClinics), 48(6), 1427-1431, 1999).

The pharmacological actions of the compound of the invention wereconfirmed by the following assays.

(1) V_(1A) Receptor Binding Assay:

A rat hepatic membrane specimen was prepared according to the method ofNakamura, et al. (Journal of Biological Chemistry, Vol. 258, No. 15, pp.9283-9289, 1983). The hepatic membrane specimen (30 μg) was incubated at25° C. for 60 minutes in a total amount of 250 μL of a 50 mM TRIS-HClbuffer solution (pH: 7.4) containing 10 mM magnesium chloride and 0.1%bovine serum albumin (BSA), together with [³H]-Arg-vasopressin(hereinafter simply referred to as “[³H]-vasopressin”) (0.5 nM, specificactivity: 75 Ci/mmol) and a test compound (from 10⁻¹⁰ to 10⁻⁶ M).Thereafter, liberated [³H]-vasopressin and receptor-binding[³H]-vasopressin were separated from each other by using a cellharvester, and the receptor-binding [³H]-vasopressin was adsorbed on aUniFilter plate, GF/B glass filter. After thoroughly drying, thereceptor-binding [³H]-vasopressin was mixed with a microplatescintillation cocktail, the amount of the receptor-binding[³H]-vasopressin was measured by using TopCount, and an inhibition ratewas calculated according to the following equation.Inhibition rate (%)=[100−(C₁−B₁)]/(C₀−B₁)×100C₁: An amount of [³H]-vasopressin binding to the membrane specimen whentreating the receptor membrane specimen in the co-presence of the testcompound having a known concentration and [³H]-vasopressinC₀: An amount of [³H]-vasopressin binding to the membrane specimen whentreating the receptor membrane specimen in the presence of[³H]-vasopressin and in the absence of the test compoundB₁: An amount of [³H]-vasopressin binding to the membrane specimen whentreating the receptor membrane specimen in the co-presence of[³H]-vasopressin and an excessive amount of vasopressin (10⁻⁶ M)

According to the foregoing equation, a concentration of the testcompound at the inhibition rate of 50% (IC₅₀ value) was calculated, fromwhich was then calculated an affinity of the test compound with thereceptor, i.e., a dissociation constant (Ki), according to the followingequation.Ki═IC ₅₀/(1+[L]/Kd)[L]: A concentration of [³H]-vasopressinKd: A dissociation constant of [³H]-vasopressin against the receptor asdetermined by the saturation binding assay

A logarithm of the Ki value as calculated according to the foregoingequation was taken, and its negative value was defined as a pKi value.

(2) V₂ Receptor Binding Assay:

A rat renal medullary membrane specimen was prepared according to themethod of Cambell, et al. (Journal of Biological Chemistry, Vol. 247,No. 19, pp. 6167-6175, 1972). The rat renal medullary membrane specimen(200 μg) was treated together with [³H]-vasopressin (0.5 nM, specificactivity: 75 Ci/mmol) and a test compound (from 10⁻¹⁰ to 10⁻⁶ M) in thesame manner as in the foregoing V_(1A) receptor binding assay, and thesame measurement was carried out to determine a pKi value.

(3) Cytochrome P450 (3A4) Inhibition Assay:

An assay was carried out according to the method of Crespi, et al.(Analytical Biochemistry, 248, 188-190, 1997). Using a 96-well plate,BFC (5×10⁻⁵ M) as a substrate, a test compound (from 9.1×10⁻⁸ to 2×10⁻⁵M), and an enzyme (10⁻⁸ M) were incubated at 37° C. for 30 minutes in atotal amount of 100 μL of a 20 mM phosphoric acid buffer solution (pH:7.4) containing 1.3 mM NADP+, 3.3 mM glucose-6-pharpahte, 3.3 mMmagnesium chloride, and 0.4 Units/mL glucose-6-phosphate dehydrogenase.Thereafter, a 100 mM TRIS buffer solution containing 80% acetonitrilewas added to stop the reaction, and a fluorescent intensity (excitationwavelength: 409 nm, fluorescent wavelength: 530 nm) was measured by afluorescent plate reader. An inhibition rate was calculated according tothe following equation, and a concentration of the test compound at theinhibition rate of 50% (IC₅₀ value) was determined.Inhibition rate (%)=[100−(C₁−B₁)]/(C₀−B₁×100C₁: A fluorescent intensity in the presence of the test compound havinga known concentration, enzyme and the substrateC₀: A fluorescent intensity in the presence of enzyme and the substrateand in the absence of the test compound

B₁: A fluorescent intensity of the blank well TABLE 1 Antagonism againstarginine vasopressin V_(1A) and V₂ receptors and inhibition actionagainst drug metabolizing enzyme CYP3A4 Inhibition activity Bindingactivity Binding activity against drug against arginine against argininemetabolizing vasopressin V_(1A) vasopressin V₂ enzyme CYP3A4 Example No.receptor (pKi) receptor (pKi) (IC₅₀/μM)  1 8.55 8.22 7.82  9 8.42 7.982.4 11 8.71 7.91 2.0 12 8.12 7.54 5.9 Control 8.11 8.07 0.21 compound1¹⁾ Control 8.91 8.98 0.43 compound 2²⁾¹⁾N-[4-(2-Benzyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl)phenyl]biphenyl-2-carboxamide hydrochloride (a compound of Example 22 asdescribed in WO 95/03305 - but the test compound is a hydrochloride)²⁾N-[4-(2-Cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl)phenyl]biphenyl-2-carboxamide hydrochloride (a compound of Example 23 asdescribed in WO 95/03305 - but the test compound is a hydrochloride)

As shown in Table 1, it has become clear that the compounds of theinvention have a superior receptor-binding activity against the V_(1A)receptor a V₂ receptor and a low inhibition activity against the drugmetabolizing enzyme CYP3A4.

The drug of the invention can be prepared by a usually employed methodusing one or two or more of the compound of the invention represented bythe general formula (I) and a pharmaceutical carrier, excipient andother additives as used for formulation. The administration may be inany form of oral administration by tablets, pills, capsules, granules,powders, liquids, etc., or parenteral administration by injections suchas intravenous or intramuscular injection, suppositories, transnasaladministration, transmucous administration, dermal administration, etc.

As a solid composition for the oral administration according to theinvention, tablets, powders, or granules are used. In such a solidcomposition, one or more active substances are mixed with at least oneinert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, andmagnesium metasilicate aluminate. The composition may contain additivesother than the inert diluent, such as a lubricant such as magnesiumstearate, a disintegrating agent such as cellulose calcium glycolate, astabilizer such as lactose, and a dissolution aid such as glutamic acidand aspartic acid, according to the customary method. If desired, thetablets or pills may be coated by a sugar coating such as sugar,gelatin, hydroxypropyl cellulose, and hydroxypropylmethyl cellulosephthalate, or a film made of a gastric-soluble or intestinal solublesubstance.

The liquid composition for oral administration contains apharmaceutically acceptable emulsion agent, solution agent, suspendingagent, syrup, or elixir and contains a generally employed inert diluentsuch as purified water and ethanol. In addition to the inert diluent,this composition may contain an auxiliary agent such as a wetting agentand a suspending agent, a sweetener, a flavor, an aromatic, or anantiseptic.

The injection for parenteral administration contains a sterile aqueousor non-aqueous solution agent, suspending agent or emulsion agent.Examples of the aqueous solution agent or suspending agent includedistilled water or physiological saline for injection. Examples of thenon-aqueous solution agent or suspending agent include propylene glycol,polyethylene glycol, vegetable oils such as olive oil, alcohols such asethanol, and Polysolvate 80. Such a composition may also contain anauxiliary agent such as an antiseptic, a wetting agent, an emulsifier, adispersing agent, a stabilizer such as lactose, and a dissolution aidsuch as glutamic acid and aspartic acid. These compositions aresterilized by, for example, filtration through a bacteria-holdingfilter, compounding with an anti-bacterial agent, or irradiation.Further, these can be used by producing a sterile solid composition anddissolving it in sterile water or a sterile solvent for injection beforethe use.

Concretely, for example, 1.0 mg of the compound of Example 6,300 mg ofpropylene glycol, and 100 mg of ethanol are mixed, to which is thenadded water for injection to make a total volume of 1 mL, whereby theinjection can be prepared.

Usually, in the case of the oral administration, it is proper that thedose of the drug per day is from about 0.0001 to 50 mg per kg,preferably from about 0.001 to 10 mg per kg, and more preferably from0.01 to 1 mg per kg of the body weight and that the drug is administeredonce or dividedly two to four times. In the case of the intravenousadministration, it is proper that the dose of the drug per day is fromabout 0.0001 to 1 mg per kg, and preferably from about 0.0001 to 0.1 mgper kg of the body weight and that the drug is administered once ordividedly several times. The dose is properly determined depending onthe individuals while taking into consideration the symptom, age andsex.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention will be specifically described below with reference to thefollowing Examples, but it should not be limited thereto. Incidentally,the production processes of the starting compounds to be used in thefollowing Examples will be described with reference to the ReferentialExamples.

Example 1N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide hydrochloride

In 30 mL of tetrahydrofuran was dissolved in 1.0 g ofN-[4-(5-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-carbonyl)phenyl]biphenyl-2-carboxamide,to which was then added 0.902 g of phenyltrimethylammonium tribromide,and the mixture was stirred at room temperature for 150 minutes. Aninsoluble matter of the reaction mixture was removed by filtration, andthe solvent was distilled off in vacuo. The resulting residue wasdissolved in 30 mL of chloroform, to which were then added 1.70 g of2-amidinopyridinium hydrochloride hydrate and 2.1 g of potassiumcarbonate, and the mixture was refluxed upon heating for 9 hours. Thereaction mixture was cooled and rinsed with water, and the chloroformlayer was dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the resulting residue was subjected to silica gelchromatography and eluted with chloroform-methanol (70:1). To the eluatewas added 0.9 mL of a 4M hydrochloric acid-ethyl acetate solution inchloroform, and the solvent was then distilled off. The resultingresidue was recrystallized from acetonitrile to obtain 0.830 g of thetitled compound.

Compounds of Examples 2 to 4 as shown in Table 2 were produced in thesame manner as in Example 1 while using the respective correspondingstarting materials.

Incidentally, the abbreviations shown below are used in the table(hereinafter the same).

Ex: Example No., Ref Referential Example No., salt: salt (nodescription: free form, HCl: hydrochloride, H₂O: hydrate), Data:Physicochemical data, MS: FAB-MS(M+H)⁺, MS-: FAB-MS(M−H)⁻, NMR: ¹H-NMR δ(ppm), m.p.: Melting point (° C.) TABLE 2

Ex R salt Data 1

HClNMR(DMSO-d₆);3.00-3.15(1H,m),3.21-3.40(2H,m),4.95-5.10(1H,m),6.87(1H,d,J=6.8Hz),6.99(2H,d,J=7.8Hz),7.18(1H,t,J=7.8Hz),7.24-7.57(12H,m),7.70(1H,dd,J=4.6Hz,7.3Hz),8.19(1H,dt,J=1.4Hz,7.8Hz),8.45(1H,d,J=7.3Hz),8.81(1H,d,J=7.8Hz),8.86(1H,d,J=4.6Hz),10.31(1H,s).MS;562. 2

HClNMR(DMSO-d₆);2.98-3.10(1H,m),3.12-3.34(2H,m),4.93-5.08(1H,m),6.79(1H,d,J=7.3Hz),6.92(2H,d,J=8.0Hz),7.02(1H,d,J=8.0Hz),7.23-7.60(12H,m),8.33(1H,d,J=8.0Hz),8.75(1H,d,J=2.2Hz),8.77-8.81(1H,m),9.56(1H,s),10.28(1H,s).MS;563. 3

HCl NMR(DMSO-d₆);2.66(3H,s),3.00-3.15(1H,m),3.20-3.37(2H,m),4.95-5.00(1H,m),6.85(1H,d,J=7.3Hz),6.97(2H,d,J=8.1Hz),7.15(1H,t,J=8.1Hz),7.25-7.58(13H,m),8.04(1H,t,J=8.1Hz),8.37(1H,d,J=8.1Hz),8.47(1H,d, J=7.3Hz),10.29(1H,s).MS-;574. 4

HClNMR(DMSO-d₆);3.00-3.12(1H,m),3.15-3.36(2H,m),4.95-5.06(1H,m),6.83(1H,d,J=7.3Hz),6.95(2H,d,J=7.3Hz),7.12(1H,t,J=7.3Hz),7.24-7.56(12H,m),7.70(1H,t,J=5.1Hz),8.29(1H,dd,J=1.4Hz,8.1Hz),9.08(2H,d,J=5.1Hz),10.29(1H,s).MS;563.

Referential Example 12-(2-Pyridyl)-1,4,5,6-tetrahydro-6-(4-methylbenzenesulfonyl)imidazo[4,5-d][1]benzazepine

In 30 mL of chloroform was dissolved 2.0 g of1,2,3,4-tetrahydro-1-(4-methylbenzenesulfonyl)-1-benzazepin-5-one, towhich was then added dropwise a solution of 0.33 mL of bromine in 10 mLof chloroform. The mixture was stirred at room temperature for one hour.The reaction mixture was rinsed with saturated sodium hydrogencarbonateand then dried over anhydrous sodium sulfate. The solvent was distilledoff, and the resulting residue was dissolved in 30 mL of chloroform. Tothe solution were added 5.0 g of 2-amidinopyridinium hydrochloridehydrate and 5.3 g of potassium carbonate, and the mixture was refluxedupon heating for 10 hours. The reaction mixture was cooled, and thesolvent was then distilled off. To the resulting residue was added 30 mLof a 1M hydrochloric acid aqueous solution, and a deposited solid wascollected by filtration. The resulting solid was suspended in chloroformand rinsed with a 1M sodium hydroxide aqueous solution, and thechloroform layer was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the resulting residue was recrystallized fromethanol to obtain 1.70 g of the titled compound.

¹H-NMR (DMSO-d₆): δ2.12 (3H, s), 3.00 to 3.33 (4H, br), 7.13 (2H, d,J=8.1 Hz), 7.21 (1H, dt, J=1.4 Hz, 8.1 Hz), 7.29 to 7.43 (5H, m), 7.89(1H, dt, J=1.4 Hz, 8.1 Hz), 8.07 (1H, d, J=8.1 Hz), 8.17 (1H, d, J=7.3Hz), 8.60 (1H, d, J=4.4 Hz)

Referential Example 22-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine

In 9 mL of sulfuric acid and 4.3 mL of acetic acid was dissolved 2.93 gof the compound of Referential Example 1, and the solution was stirredupon heating on a water bath at 70° C. for 90 minutes. The reactionmixture was poured into 100 mL of ice water, to which was then added a10M sodium hydroxide aqueous solution to make the mixture basic. Afterfurther adding 200 mL of methyl ethyl ketone, the mixture was subjectedto liquid-liquid separation. The organic layer was rinsed with saturatedsalt water and then dried over anhydrous sodium sulfate. The solvent wasdistilled off, and the resulting residue was crystallized from ethylacetate. A deposited crystal was collected by filtration and dried toobtain 1.038 g of the titled compound.

¹H-NMR (DMSO-d₆): δ2.97 (2H, t, J=5.1 Hz), 3.20 to 3.26 (2H, m), 5.95(1H, t, J=3.7 Hz), 6.73 to 6.82 (2H, m), 6.93 (1H, dt, J=1.5 Hz, 7.3Hz), 7.34 (1H, dd, J=4.4 Hz, 8.1 Hz), 7.86 (1H, dt, J=1.5 Hz, 8.1 Hz),8.11 (1H, d, J=8.1 Hz), 8.24 (1H, dd, J=1.5 Hz, 8.1 Hz), 8.59 (1H, d,J=4.4 Hz), 12,67 (1H, s)

Referential Example 3 Methyl4-[(biphenyl-2-carbonyl)amino]-2-fluorobenzoate

To a solution of 0.66 g of 2-phenylbenzoic acid, 07 mL oftetrahydrofuran, and one drop of N,N-dimethylformamide was added 0.29 mLof thionyl chloride under ice cooling, and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated in vacuo, 3 mL of toluene was added to the residue, and themixture was again concentrated in vacuo. The resulting residue wasdissolved in 3 mL of chloroform, and the solution was added dropwise toa chloroform solution (6 mL) containing 0.56 g of methyl4-amino-2-fluorobenzoate and 0.63 mL of dimethylaniline under icecooling. The mixture was stirred at room temperature for 4 hours. Thereaction mixture was diluted with ethyl acetate, and the organic layerwas rinsed with a 1M hydrochloric acid aqueous solution and a 1M sodiumhydroxide aqueous solution. The organic layer was dried over anhydroussodium sulfate, and the solvent was then distilled off in vacuo. Theresulting residue was subjected to silica gel chromatography and elutedwith hexane-ethyl acetate (3:1) to obtain 1.00 g of the titled compound.

Compounds of Referential Examples 4 to 7 as shown in Table 3 wereproduced in the same manner as in Referential Example 3 while using therespective corresponding starting materials. TABLE 3

Ref R³ D R′ Data 3 H

Me NMR(CDCl₃);3.88(3H,s),6.64(1H,d,J=8.4Hz),7.01-7.13(1H;m),7.40-7.61(8H,m),7.72-7.80(1H,m),7.87-7.94(1H,m). 4 H

Me NMR(CDCl₃);3.86(3H,s), 7.91(2H,s),7.18-7.54(13H,m),7.63-7.68(1H,m),7.80 (1H,dd,J=1.7Hz,7.5Hz),7.86(1H,s),8.59(1H,d,J=8.4Hz). 5 2-F

Et NMR(CDCl₃);1.37(3H,t, J=7.1Hz),4.33(2H,q,J=7.1Hz),7.11(1H,ddd,J=1.1Hz, 8.0Hz,9.5Hz),7.22(1H,dd,J=1.1Hz,7.5Hz),7.28-7.45 (5H,m),7.52-7.58(2H,m), 7.86(1H,dd)J=1.5Hz,7.7Hz),7.90-7.95(2H,m). 6 H

Me NMR(CDCl₃);3.90(3H,s),6.81(1H,d,J=7.9Hz),7.05-7.13(1H,m),7.18-7.59(4H, m),7.83(1H,m),8.21(1H,ddd,J=2.0Hz,8.8Hz,11.2Hz),8.25-8.33(2H,m),8.64-8.67(1H,m),8.77(1H,d,J=2.0Hz). 7 H

Me NMR(CDCl₃);3.95(3H,s),7.24-7.71(9H,m),7.88-7.94(1H,m),8.04(1H,d,J=8.6Hz),8.53-8.58(1H,m).

Referential Example 8 4-[(Biphenyl-2-carbonyl)amino]-2-fluorobenzoicacid

In 10 mL of ethanol was dissolved 1.00 g of the compound of ReferentialExample 3, to which was then added 4.35 mL of a 1M sodium hydroxideaqueous solution. The reaction mixture was stirred at room temperaturefor 2 days. A 1M hydrochloric acid aqueous solution was added to thereaction mixture to make it have a pH of 6, and a deposited solid wascollected by filtration. The resulting solid was recrystallized fromethyl acetate to obtain 0.77 g of the titled compound.

Compounds of Referential Examples 9 to 12 as shown in Table 4 wereproduced in the same manner as in Referential Example 8 while using therespective corresponding starting materials. TABLE 4

Ref R³ D Data 8 H

m.p.:233-235° C. 9 H

m.p.:162-164° C. 10 2-F

m.p.:219-222° C. 11 H

m.p.:86-89° C. 12 H

m.p.113-116° C.

Example 5N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide monohydrate

To a suspension of 3.60 g of 4-[(biphenyl-2-carbonyl)amino]benzoic acid,100 mL of tetrahydrofuran, and one drop of N,N-dimethylformamide wasadded 1.21 mL of thionyl chloride under ice cooling, and the reactionmixture was stirred at room temperature for 2 hours 30 minutes. Thereaction mixture was concentrated in vacuo, 5 mL of toluene was added tothe residue, and the mixture was again concentrated in vacuo. To theresulting residue was added an acetonitrile solution (90 mL) of 2.84 gof the compound of Referential Example 2, and the mixture was stirredupon heating on a water bath at 80° C. for 17 hours 30 minutes. Thereaction mixture was cooled to room temperature, and a depositedprecipitate was collected by filtration and rinsed with acetonitrile.The resulting solid was suspended in a 1M sodium hydroxide aqueoussolution and then extracted with chloroform. The chloroform layer wasdried over anhydrous sodium sulfate, and the solvent was distilled offin vacuo. The resulting residue was crystallized from ethyl acetate toobtain 4.921 g of the titled compound.

¹H-NMR(DMSO-d₆): δ2.61 to 3.30 (3H, m), 4.93 to 5.40 (1H, m), 6.72 (1H,d, J=7.3 Hz), 6.88 (2H, d, J=7.8 Hz), 6.96 (1H, t, J=7.8 Hz), 7.24 to7.56 (13H, m), 7.94 (1H, dt, J=2.0 Hz, 7.8 Hz), 8.19 (1H, d, J=7.8 Hz),8.29 (1H, d, J=7.3 Hz), 8.65 (1H, d, J=4.4 Hz), 10.28 (1H, s), 13.05(1H, s)

FAB-MS(M+H)⁺: 562

Elemental analysis as C₃₆H₂₇N₅O₂·H₂O:

(Calculated): C: 74.59%, H: 5.04%, N: 12.08%, O: 8.28%

(Found): C: 74.89%, H: 5.01%, N: 12.15%

Example 6N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide

To 1.0 g of the compound of Example 5 was added 20 mL of acetonitrile,and the mixture was stirred upon heating on an oil bath at 95° C. for 35minutes. The suspension was cooled to room temperature, and aprecipitate was collected by filtration and rinsed with 6 mL ofacetonitrile to obtain 0.85 g of the titled compound.

¹H-NMR (DMSO-d₆): δ2.97 to 3.26 (3H, m), 4.97 to 5.00 (1H, m), 6.71 (1H,d, J=7.6 Hz), 6.88 (2H, d, J=8.4 Hz), 6.95 (1H, t, J=7.6 Hz), 7.24 to7.57 (13H, m), 7.94 (1H, dt, J=1.6 Hz, 7.6 Hz), 8.18 (1H, d, J=7.6 Hz),8.30 (1H, d, J=8.0 Hz), 8.63 (1H, d, J=4.8 Hz), 10.27 (1H, s), 13.03(1H, s)

FAB-MS(M+H)⁺: 562

Melting point: 240 to 242° C.

Elemental analysis as C₃₆H₂₇N₅O₂

(Calculated): C: 76.99%, H: 4.85%, N: 12.47%, O: 5.70%

(Found): C: 77.08%, H: 4.93%; N: 12.39%

Example 7N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide hydrochloride

To a suspension of 0.605 g of 4-[(biphenyl-2-carbonyl)amino]benzoicacid, 10 mL of tetrahydrofuran, and one drop of N,N-dimethylformamidewas added 0.167 mL of ice-cooled thionly chloride, and the reactionmixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated in vacuo, 5 mL of toluene was added to theresidue, and the mixture was again concentrated in vacuo. To theresulting residue was added an acetonitrile solution (25 mL) of 0.385 gof the compound of Referential Example 2, and the mixture was stirredupon heating on a water bath at 80° C. for 4 hours. The reaction mixturewas cooled to room temperature, and a deposited precipitate wascollected by filtration and rinsed with acetonitrile. The resultingsolid was suspended in a 1M sodium hydroxide aqueous solution andextracted with chloroform. The chloroform layer was dried over anhydroussodium sulfate, and the solvent was distilled off in vacuo. Theresulting residue was subjected to silica gel column chromatography andeluted with chloroform-methanol (49:1). The eluate was concentrated invacuo, and the resulting residue was crystallized from ethyl acetate toobtain 0.566 g ofN-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide.The resulting crystal was suspended in an ethyl acetate-methanol mixedsolution, to which was then added 0.277 mL of a 4M hydrochloricacid-ethyl acetate solution, and the solvent was distilled off in vacuo.The resulting residue was suspended in 20 mL of ethanol, and thesuspension was stirred upon heating on a water bath at 80° C. for 10minutes. The suspension was cooled to room temperature, and aprecipitate was collected by filtration and rinsed with ethanol toobtain 0.350 g of the titled compound.

The physicochemical data of Example 7 were identical with those ofExample 1.

Compounds of Examples 8 to 11 and a compound of Referential Example 13as shown in Table 5 were produced in the same manner as in Example 7while using the respective corresponding starting materials.

Example 12N-{2-Hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]-benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamidehydrochloride

In 6 mL of trilfuoroacetic acid was dissolved 0.525 g of the compound ofReferential Example 13, to which was then added 0.466 g ofpentamethylbenzne. The reaction mixture was stirred at room temperaturefor 3 hours, and 0.233 g of pentamethylbenzene was further added to thereaction mixture. The reaction mixture was stirred at room temperaturefor an additional 21 hours. The reaction mixture was concentrated invacuo, 3 mL of toluene was added to the residue, and the mixture wasagain concentrated in vacuo. The resulting residue was dissolved in 10mL of chloroform, to which was then added 10 mL of a 1M sodium hydroxideaqueous solution, and a deposited solid was collected by filtration. Tothe resulting solid was added 0.20 mL of a 4M hydrochloric acid-ethylacetate solution, and the solvent was distilled off. The resultingresidue was recrystallized from ethanol to obtain 0.300 g of the titledcompound. TABLE 5 R³ D salt Data Ex 8 H

HCl NMR(DMSO-d₆);3.08-3.28(2H,m),3.30-3.42 (1H,m),4.88-4.98(1H,m),6.92(1H,d,J=8.1Hz), 7.08-7.18(2H,m),7.25(1H,d,J=8.0Hz),7.28-7.40(7H,m),7.47(2H,t,J=8.1Hz),7.54-7.60(2H,m),7.63-7.68(1H,m),8.15 (1H,t,J=6.6Hz),8.33(1H, d,J=8.0Hz),8.60(1H,d,J=7.3Hz),8.82(1H,d,J=4.4Hz),10.45(1H,s). MS;580. Ex 9 2-F

HCl NMR(DMSO-d₆);2.97-3.14(1H,m),3.18-3.40 (2H,m),4.90-5.11(1H,m),6.86(1H,d,J=7.3Hz), 6.98(2H,d,J=7.3Hz),7.10-7.21(3H,m),7.28-7.43(6H,m),7.48-7.68 (4H,m),8.16(1H,t,J=7.3Hz),8.42(1H,d,J=8.1Hz), 8.73(1H,d,J=7.3Hz),8.83 (1H,d,J=4.4Hz),10.36(1H,s).MS;580. Ex 10 H

HCl NMR(DMSO-d₆);3.05-3.18(1H,m),3.19-3.40 (2H,m),4.93-5.08(1H,m),6.96(1H,d,J=8.0Hz), 7.19(1H,t,J=7.4Hz), 7.24-7.57(11H,m),7.61(1H,dd,J=7.1Hz,7.3Hz), 7.74-7.82(1H,m),7.83-7.89(1H,m),8.15(1H,dt,J=1.6Hz,8.0Hz),8.40(1H, d,J=8.0Hz),8.58-8.68 (1H,m),8.81(1H,d,J=4.4Hz),10.75(1H,s).MS;563. Ex 11 H

HCl NMR(DMSO-d₆);3.10 (1H,dt,J=2.9Hz,13.2Hz), 3.02-3.40(2H,m),4.98(1H,dd,J=5.2Hz,13.2Hz), 6.77(1H,d,J=8.0Hz),7.09(1H,t,J=7.3Hz),7.24-7.69(13H,m),7.90(1H,dd, J=2.2Hz,8.8Hz),8.14(1H,t,J=7.3Hz),8.30(1H,d,J=7.3Hz),8.56(1H,d,J=8.1 Hz),8.81(1H,d,J=4.4Hz),10.47(1H,s).MS;563. Ex 13 H

NMR(DMSO-d₆);2.96-3.20(3H,m),4.87-4.99 (1H,m),6.34(1H,brs),6.65-6.78(2H,m),6.94-7.02(1H,m),7.08-7.50 (15H,m),7.55(1H,t,J=7.0Hz),7.64-7.71(1H,m), 7.94(1H,dt,J=1.7Hz,7.7 Hz),8.23(1H,d,J=8.1Hz),8.31(1H,s),8.35-8.41 (1H,m),8.65-8.72(1H, m),9.06(1H,brs),13.06(1H,brs). Ex 12 H

HCl NMR(DMSO-d₆);2.98-3.10(1H,m),3.17-3.25 (2H,m),4.90-5.08(1H,m),6.34(1H,d,J=5.9Hz), 6.76(1H,s),6.82-6.90 (1H,m),7.15(1H,t,J=7.3Hz),7.26-7.49(8H,m), 7.53-7.59(2H,m),7.65 (1H,dd,J=5.1Hz,7.3Hz),8.15(1H,t,J=8.8Hz),8.50 (1H,d,J=8.1Hz),8.75-8.85(2H,m),9.13(1H,s),10.00(1H,s).MS;578.

Structures of other compounds of the invention will be shown in Tables 6to 8. These compounds can be easily synthesized in the foregoingproduction processes or the processes as described in the Examples, orby undergoing slight modifications within the range obvious to thoseskilled in the art.

Incidentally, the term “No” in the tables means a compound number. TABLE6

No X Y R¹¹ R¹² P Q R³¹ R³² A1 CH N H H CH CH F H A2 CH N H H CF CH H HA3 CH N H H N CH H H A4 CH N H H CH N H H A5 CH N H H CH C(OH) H H A6 NCH H H CH CH F H A7 N CH H H CF CH H H A8 N CH H H N CH H H A9 N CH H HCH N H H A10 N CH H H CH C(OH) H H A11 CH CH CH₃ H CH CH F H A12 CH CHCH₃ H CF CH H H A13 CH CH CH₃ H N CH H H A14 CH CH CH₃ H CH N H H A15 CHCH CH₃ H CH C(OH) H H A16 CH CH H H CH CH Cl H A17 CH CH H H CH CH H ClA18 CH CH H H CH CH OH H A19 CH CH H H CH CH H OH A20 CH CH Cl H CH CH HH A21 CH CH H CH3 CH CH H H

TABLE 7

No X Y R¹¹ P Q R T R³¹ A22 CH CH H CH CH CH CH F A23 CH CH H CH CH CH CHH A24 CH CH H N CH CH CH H A25 CH CH H CH N CH CH H A26 CH CH H CH CH NCH H A27 CH CH H CH CH CH N H A28 CH CH H CF CH CH CH H A29 N CH H CH CHCH CH H A30 CH N H CH CH CH CH H A31 CH CH CH₃ CH CH CH CH H

TABLE 8

No X Y R¹¹ P Q R T R³¹ A32 CH CH H CH CH CH CH F A33 CH CH H CH CH CH CHH A34 CH CH H N CH CH CH H A35 CH CH H CH N CH CH H A36 CH CH H CH CH NCH H A37 CH CH H CH CH CH N H A38 CH CH H CF CH CH CH H A39 N CH H CH CHCH CH H A40 CH N H CH CH CH CH H A41 CH CH CH₃ CH CH CH CH H

1-8. (canceled)
 9. A method of antagonizing an arginine vasopressin receptor, comprising: contacting the arginine vasopressin receptor with a composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the ring D represents phenylene or pyridinediyl; X and Y may be the same or different and each represents CH or N; and R¹, R² and R³ may be the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen, or a lower alkyl; and a pharmaceutical carrier or excipient.
 10. The method of claim 9, wherein the ring D represents 1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl.
 11. The method of claim 10, wherein X and Y each represents CH, and R¹ represents a hydrogen atom.
 12. The method of claim 11, wherein the ring D represents 1,4-phenylene, and R² and R³ each represents a hydrogen atom.
 13. The method of claim 9, wherein the compound is: N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, N-{3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, 2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, N{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-2-pyridyl}biphenyl-2-carboxamide, N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-3-pyridyl}biphenyl-2-carboxamide, or N-{2-hydroxy4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide.
 14. A method of treating heart failure or hyponatremia, comprising administering to a patient in need thereof a composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the ring D represents phenylene or pyridinediyl; X and Y may be the same or different and each represents CH or N; and R¹, R² and R³ may be the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen, or a lower alkyl; and a pharmaceutical carrier or excipient.
 15. The method of claim 14, wherein the ring D represents 1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl.
 16. The method of claim 15, wherein X and Y each represents CH, and R¹ represents a hydrogen atom.
 17. The method of claim 16, wherein the ring D represents 1,4-phenylene, and R² and R³ each represents a hydrogen atom.
 18. The method of claim 14, wherein the compound is: N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, N-{3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, 2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide, N-{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-2-pyridyl}biphenyl-2-carboxamide, N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-3-pyridyl}biphenyl-2-carboxamide, or N-{2-hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide. 